Much has been learned about how episodic memory is encoded in the hippocampus (reviewed in (Hell & Ehlers, 2008). In this structure, the strength of synapses can be changed by experience through a process called long-term potentiation (LTP). It has been shown that mutations that interfere with LTP produce profound deficits in memory (Giese, Fedorov, Filipkowski, & Silva, 1998). There has therefore been a great deal of effort to understand the cellular and molecular mechanisms of this process. The LTP in the stratum radiatum of the CA1 hippocampal region has served as the model system for the field. An important insight is that LTP has both early and late phases, and that these two phases have very different properties. Early LTP (˜1 hr) depends on modifications of the existing synaptic structure (e.g., phosphorylation of GluR1 and stargazin (Nicoll, 2003)), whereas late LTP depends on protein synthesis and trans-synaptic enlargement of the synapse (Bosch et al., 2014).
The neuromodulator dopamine has been shown to have a necessary role in late LTP and late memory. It has been shown that late LTP (but not early LTP) is strongly inhibited by dopamine (D1) antagonists (Frey, Schroeder, & Matthies, 1990; Gao et al., 2009; Huang & Kandel, 1995; Li, Cullen, Anwyl, & Rowan, 2003; Otmakhova & Lisman, 1998)). This dopamine requirement has been further verified by knockout of dopamine receptors, by dopamine depletion experiments (reviewed by (Lisman et al., 2011)) and by reducing D1 receptors using siRNA (Ortiz et al., 2010). The present disclosure relates to technologies that can increase dopamine levels and/or can otherwise improve memory or treat one or more diseases, disorders or conditions including, for example, Alzheimer's disease.